The overall objective of this proposal is to identify novel vaccine candidates for human falciparum malaria. Human residents of endemic areas develop protective immunity that limits parasitemia and disease, and naturally acquired human immunity provides an attractive model for vaccine development. In this application, we propose to capitalize on the sera, and parasitologic, and epidemiologic data which we collected on a previously studied cohort and use these materials to identify new vaccine candidates for P. falciparum. In previous studies, we have evaluated the role of immune responses to several known malaria vaccine candidates in mediating resistance to reinfection in a cohort of volunteers living in a holoendemic area of western Kenya. As part of this previous study, 143 male volunteers aged 12-35 yr. were drug-cured of current malaria infection and followed for 16 weeks with weekly blood smears to detect reinfection. Two weeks after drug treatment, but before reinfection, 10 mL of blood was obtained from each volunteer. Detailed descriptive epidemiologic aspects of these volunteers were documented, volunteers' resistance to reinfection with P. falciparum was precisely measured, and a complete serum and PBMC bank was established. Using this serum bank, we now propose to perform differential screening of a P. falciparum cDNA expression library with sera pooled from the most resistant individuals and contrasting these results using sera pooled from the most susceptible volunteers. These initial experiments will identify genes whose protein products are preferentially recognized by antibodies in the sera of humans with a high level of naturally acquired resistance to P. falciparum infection. These gene products represent rationally identified vaccine candidates. Subsequent experiments will evaluate the relationship between humoral and cellular immune recognition of these candidates and resistance to reinfection in the entire cohort of 143 volunteers.